an anticancer protein’s chequered past and promising future

Cartoon characterizing p53 as a masked superhero

Illustration: Andrew Khosravani

When scientists first got here throughout p53 in 1979, it was an intriguing however not Earth-shattering discovery. Six teams independently found a mobile protein with a molecular weight of roughly 53 kilodaltons — therefore the identify. It appeared that p53 was interacting with a tumour-inducing virus known as simian virus 40, and researchers quickly confirmed that wholesome cells pressured to specific this newly cloned gene encoding p53 rapidly turned cancerous1.

However the reality was extra difficult. As extra researchers started to review p53, it turned obvious that the tumour-causing variations of the gene had been really mutated. The unmutated, or wild-type, model of the gene, which was cloned from people and mice within the Eighties, exerted the precise reverse impact: the gene acted as a potent inhibitor of tumorigenesis2. Scientists had even obtained its dimension flawed; p53’s true molecular weight is nearer to 44 kilodaltons.

Within the three a long time since researchers got here to this realization, p53’s organic significance has change into ever extra obvious. The protein coordinates a variety of important mobile features, and its evolutionary historical past dates again to a few of the earliest multicellular life on Earth. More often than not, p53 is stored in an inhibited state at low ranges within the cell till it’s required. Environmental stress, irregular metabolic exercise, genetic injury and superior ageing can all set off the protein’s activation, enabling p53 to straight regulate the expression of lots of of genes to provoke an acceptable response.

Some mobile crises could be minor, requiring a response targeted on restore to revive mobile operate. Catastrophic issues, nonetheless, may lead a cell to self-destruct to forestall additional hurt.

These features make p53 an important defence towards organic and environmental insults that may give rise to most cancers, main some folks to dub the protein ‘the guardian of the genome’. As demonstrated by these early research of mutant types of the TP53 gene, mutations that intrude with the operate of p53 are well-known drivers of most cancers. Roughly half of all cancers are related to p53 mutations3, and practically 90% of individuals born with such mutations — a uncommon hereditary situation often called Li–Fraumeni Syndrome — will develop most cancers of their lifetime. And even when p53 itself stays intact, different elements can preserve it shackled and depart cells vulnerable to tumorigenesis.

Regardless of a formidable file of analysis into the operate of p53 and its myriad mutants, there are nonetheless no accredited medication that may selectively goal the p53 pathway in most cancers. However there are some promising avenues of assault, together with molecules that neutralize the disruptive results of particular p53 mutations or that counteract the extreme inhibition of p53 seen in some tumours. Additional advances in these and different therapeutic approaches — and the identification of well-chosen mixture therapies — may in the end result in a serious victory towards a broad vary of tumour varieties.

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